Quantification of gold nanoparticle photon radiosensitization from direct and indirect effects using a complete human genome single cell model based on Geant4

Abstract

To investigate the radiosensitization properties of gold nanoparticles (GNPs) and better understand the intricate deoxyribonucleic acid (DNA) damage induction mechanisms involved in GNP-aided radiotherapy, a single cell model with complete human genome based on the Geant4 Monte Carlo toolkit was applied. Materials and methods: A Geant4-DNA model was implemented to simulate direct and indirect DNA damage generated in the physical and chemical stages. In the physical stage, a mixed-physics approach was taken by using Geant4-DNA in water and Livermore in gold. Water radiolysis was created posteriorly in the physicochemical and chemical stages to simulate indirect damage from reactions between DNA molecules and OH• radicals. A mono-energetic photon beam (100 keV) and two clinical photon sources (250-kVp, 6-MV flattening-filter free) were simulated for modeling the irradiation of a single cell with or without GNPs. In order to study the effects of GNP size on radiosensitization, 15, 30, and 100 nm GNPs were simulated. The effects of intracellular distribution were simulated using 90-nm GNPs with different characteristics of distribution within the cell. The time dependence of DNA damage enhancement was also studied with chemistry stage simulation end-time no larger than 10 ns. Results: Double strand break (DSB) enhancement due to direct and indirect action was quantified under different scenarios. Under realistic cellular uptake condition, the 100-nm GNPs had the most significant increase in DSBs: 40.9% and 28.5% for 100 keV and 250-kVp photon irradiation, respectively. The intracellular localization showed differing levels of radiosensitization with a maximum of 64%, 27%, and 6% DSB enhancements for 100 keV, 250-kVp, and 6-MV respectively, when 90-nm GNPs congregate around the nucleus. Conclusion:The results indicate that photon energy, GNP size, and intracellular distribution play an important role in the enhancement of DSB from direct and indirect damage under scenarios close to cell experiments. The radiosensitization effects due to indirect damage are significant and should be considered carefully.

Multiscale Monte Carlo simulations of gold nanoparticle dose‐enhanced radiotherapy I: Cellular dose enhancement in microscopic models

“…For example, following Equation (), the number of 25 nm radius GNPs ( n GNP ) in a 5, 7.35 or 10 µm radius cell would be 1.96 × 10 4 , 5.27 × 10 4 , and 1.21 × 10 4 , respectively, to achieve a concentration of 20 mg/g. These numbers are consistent with the expected range for 50 nm diameter GNPs established by Zhao et al 8 . (see Figure 3 in that work).…”

“…31,32 It is also important to note that in vivo uptake to tumor (and other organs) can vary significantly from the injected GNP concentration. Zhao et al 8 established a range of approximately 10,000-50,000 GNPs per cell for 50 nm radius GNPs based on the in vitro works of Chithrani et al 33 and Peretz et al 34 ; this is consistent with our range of 10,540-63,240 GNPs per cell for the nominal cell size (Equation 1). Hainfeld et al 35 demonstrated tumor uptake of up to 15 mg/g after the injection of 11 nm GNPs at 4 g/kg mouse bodyweight.…”

“…Jones et al 7 performed simulations of discrete GNPs, using the dose kernel around a single GNP to extrapolate dose enhancement on a larger scale, but neglecting the shielding effects of neighboring GNPs. Zhao et al 8 used a single cell model containing discrete GNPs of different sizes in various configurations to model DNA double strand breaks at two beam energies, but ignored effects of GNPs in one cell on neighboring cells. Kirkby and Ghasroddashti 9 assessed mitochondrial dose enhancement, investigating different source spectra and varying GNP and mitochondria dimensions using a mathematical model to combine macroscopic fluence with mitochondrial dose calculations.…”

“…performed simulations of discrete GNPs, using the dose kernel around a single GNP to extrapolate dose enhancement on a larger scale, but neglecting the shielding effects of neighboring GNPs. Zhao et al 8 . used a single cell model containing discrete GNPs of different sizes in various configurations to model DNA double strand breaks at two beam energies, but ignored effects of GNPs in one cell on neighboring cells.…”

“…Figure 7: DEFs as a function of energy for (a) nucleus and (b) cytoplasm of the (red) small cells, (r cell , r nuc ) = (5, 2), (5, 3), (5, 4) µm, and the (blue) large cells, (10, 7),(10,8), and (10, 9) µm, as well as the (green) reference cell,(7.35, 5) µm, for 20 mg/g and gold in the "peri" configuration.…”